DESCRIPTION: (Applicant's Abstract) Mammalian brain dopamine system is a critical modulator of a wide variety of brain functions, including movement control, reward and motivation, thought process, and learning and memory. Psychoactive drugs cocaine and amphetamine act through the brain dopamine system, and wide-spread drug abuse is a major concern in our society. Understanding the molecular mechanisms underlying dopamine system signal transduction which modulate various brain functions in both normal and drug stimulated states is crucial for developing methods for the prevention and treatment of drug abuse. D1 dopamine receptor is highly expressed and widely distributed in the brain. Stimulation of D1 receptor has been shown to couple to multiple second messenger systems in transfected cells and is necessary for locomotor stimulant effect of cocaine. However, the molecular mechanisms and the regulation of D1 receptor signaling in normal and cocaine treated brains are unclear. Our working hypothesis is that multiple D1 dopamine receptor-interacting proteins are involved in both the signal transduction from the D1 receptor, and the regulation of the signal transduction process. The scope of this proposal is to use a novel molecular approach, the yeast two-hybrid system, to identify genes encoding the D1 receptor-interacting proteins. We will study the roles of these genes in D1 receptor signaling in transfected cells, and investigate the expression of these genes in both wild-type and D1 receptor knockout mice. Furthermore, we will study the expression of these genes in both of these mice upon cocaine treatments. The completion of these studies may lead to new insights into the mechanisms of dopaminergic signal transduction and new approaches for potential treatment of drug abuse.